Selective Disruption of Respiratory Supercomplexes as a New Strategy to Suppress Her2high Breast Cancer.

AIMS Expression of the HER2 oncogene in breast cancer is associated with resistance to treatment, and Her2 may regulate bioenergetics. Therefore, we investigated whether disruption of the electron transport chain (ETC) is a viable strategy to eliminate Her2high disease. RESULTS We demonstrate that Her2high cells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs in Her2high background in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2high cells to MitoTam is dependent on the mitochondrial fraction of Her2. INNOVATION Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam. CONCLUSION We propose that the ETC is a suitable therapeutic target in Her2high disease. Antioxid. Redox Signal. 26, 84-103.

[1]  J. Neuzil,et al.  The role of Her2 and other oncogenes of the PI3K/AKT pathway in mitochondria , 2016, Biological chemistry.

[2]  M. Reni,et al.  (Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial , 2015, Clinical Cancer Research.

[3]  R. Deberardinis,et al.  Oxidative stress inhibits distant metastasis by human melanoma cells , 2015, Nature.

[4]  Andrea Viale,et al.  Tumors and mitochondrial respiration: a neglected connection. , 2015, Cancer research.

[5]  M. V. Heiden,et al.  Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells , 2015, Cell.

[6]  A. Zwinderman,et al.  Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. , 2015, The Lancet. Oncology.

[7]  D. Sabatini,et al.  An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis , 2015, Cell.

[8]  E. Gottlieb,et al.  Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation , 2015, Cell Death and Disease.

[9]  J. Neuzil,et al.  Mitochondrially targeted vitamin E succinate modulates expression of mitochondrial DNA transcripts and mitochondrial biogenesis. , 2015, Antioxidants & redox signaling.

[10]  David A. Eccles,et al.  Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. , 2015, Cell metabolism.

[11]  H. Schwalbe,et al.  Mechanistic insight from the crystal structure of mitochondrial complex I , 2015, Science.

[12]  D. Wolf.  Is reliance on mitochondrial respiration a "chink in the armor" of therapy-resistant cancer? , 2014, Cancer cell.

[13]  R. Kalluri,et al.  PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation to promote metastasis , 2014, Nature Cell Biology.

[14]  John M. Asara,et al.  Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function , 2014, Nature.

[15]  Eun Mi Kim,et al.  Nuclear and cytoplasmic p53 suppress cell invasion by inhibiting respiratory Complex-I activity via Bcl-2 family proteins , 2014, Oncotarget.

[16]  A. Jemal,et al.  Cancer treatment and survivorship statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[17]  J. Neuzil,et al.  Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans. , 2014, Free radical biology & medicine.

[18]  Guy Jerusalem,et al.  Phase Ib Study of Buparlisib plus Trastuzumab in Patients with HER2-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy , 2014, Clinical Cancer Research.

[19]  M. L. Genova,et al.  Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I. , 2013, Antioxidants & redox signaling.

[20]  Lorraine L. Lipscombe,et al.  Association Between Metformin Therapy and Mortality After Breast Cancer , 2013, Diabetes Care.

[21]  P. Dent,et al.  Mitochondrial Localized Stat3 Promotes Breast Cancer Growth via Phosphorylation of Serine 727* , 2013, The Journal of Biological Chemistry.

[22]  C. López-Otín,et al.  Supercomplex Assembly Determines Electron Flux in the Mitochondrial Electron Transport Chain , 2013, Science.

[23]  P. Gimotty,et al.  Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. , 2013, Cancer cell.

[24]  Jun S. Song,et al.  Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. , 2013, Cancer cell.

[25]  T. Yagi,et al.  Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. , 2013, The Journal of clinical investigation.

[26]  J. Neuzil,et al.  Targeting the mitochondrial electron transport chain complexes for the induction of apoptosis and cancer treatment. , 2013, Current pharmaceutical biotechnology.

[27]  J. Neuzil,et al.  Mitochondrial targeting overcomes ABCA1-dependent resistance of lung carcinoma to α-tocopheryl succinate , 2013, Apoptosis.

[28]  V. Pertegato,et al.  Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells , 2012, Nature Protocols.

[29]  F. Fontanesi,et al.  Mitochondrial complex I plays an essential role in human respirasome assembly. , 2012, Cell metabolism.

[30]  L. Pannell,et al.  Receptor Tyrosine Kinase ErbB2 Translocates into Mitochondria and Regulates Cellular Metabolism , 2012, Nature Communications.

[31]  C. Sen,et al.  Mitochondrially targeted α-tocopheryl succinate is antiangiogenic: potential benefit against tumor angiogenesis but caution against wound healing. , 2011, Antioxidants & redox signaling.

[32]  J. Neuzil,et al.  Anticancer drugs targeting the mitochondrial electron transport chain. , 2011, Antioxidants & redox signaling.

[33]  W. Kühlbrandt,et al.  Arrangement of electron transport chain components in bovine mitochondrial supercomplex I1III2IV1 , 2011, The EMBO journal.

[34]  M. Brand,et al.  Evidence for Two Sites of Superoxide Production by Mitochondrial NADH-Ubiquinone Oxidoreductase (Complex I)* , 2011, The Journal of Biological Chemistry.

[35]  B. Zhivotovsky,et al.  Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: a new paradigm for effective cancer therapy. , 2011, Free radical biology & medicine.

[36]  R. Moreno-Sánchez,et al.  Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial Complex II* , 2010, The Journal of Biological Chemistry.

[37]  Mark Gerstein,et al.  3V: cavity, channel and cleft volume calculator and extractor , 2010, Nucleic Acids Res..

[38]  W. Wheaton,et al.  Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity , 2010, Proceedings of the National Academy of Sciences.

[39]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[40]  Hanna Y. Irie,et al.  Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment , 2009, Nature.

[41]  R. Moreno-Sánchez,et al.  Suppression of Tumor Growth In vivo by the Mitocan α-tocopheryl Succinate Requires Respiratory Complex II , 2009, Clinical Cancer Research.

[42]  J. Enríquez,et al.  Respiratory active mitochondrial supercomplexes. , 2008, Molecular cell.

[43]  F. Domann,et al.  α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II , 2008, Oncogene.

[44]  A. Starkov,et al.  The mitochondrial respiratory chain is a modulator of apoptosis , 2007, The Journal of cell biology.

[45]  J. Černý,et al.  Resolution of identity density functional theory augmented with an empirical dispersion term (RI-DFT-D): a promising tool for studying isolated small peptides. , 2007, The journal of physical chemistry. A.

[46]  Robin A. J. Smith,et al.  Targeting antioxidants to mitochondria by conjugation to lipophilic cations. , 2007, Annual review of pharmacology and toxicology.

[47]  J. Hirst,et al.  The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Catarina R. Oliveira,et al.  Tamoxifen and Estradiol Interact with the Flavin Mononucleotide Site of Complex I Leading to Mitochondrial Failure* , 2006, Journal of Biological Chemistry.

[49]  G. Dontu,et al.  In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. , 2003, Genes & development.

[50]  R. Coffey,et al.  Induction of cancer cell apoptosis by α‐tocopheryl succinate: molecular pathways and structural requirements , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[51]  J. Neuzil,et al.  Selective cancer cell killing by α-tocopheryl succinate , 2001, British Journal of Cancer.

[52]  S. Ostrand-Rosenberg,et al.  Mouse 4T1 Breast Tumor Model , 2000, Current protocols in immunology.

[53]  R. Cardiff,et al.  Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[54]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[55]  J. Mascarello,et al.  Respiration-deficient Chinese hamster cell mutants: Genetic characterization , 1979, Somatic cell genetics.

[56]  G. Ditta,et al.  Mammalian cells with defective mitochondrial functions: a Chinese hamster mutant cell line lacking succinate dehydrogenase activity , 1977, Cell.

[57]  J. Neuzil,et al.  Evaluation of respiration of mitochondria in cancer cells exposed to mitochondria-targeted agents. , 2015, Methods in molecular biology.

[58]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[59]  E. Gnaiger,et al.  High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. , 2012, Methods in molecular biology.

[60]  G. Hortobagyi,et al.  Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.